Phenocopies of poor metabolizers of omeprazole caused by liver disease and drug treatment

The kinetics of omeprazole and itsprimary metabolites 5′-hydroxyomeprazole and omeprazole sulfone were studied in healthy volunteers to evaluate omeprazole as a probe drug for the S-mephenytoin hydroxylase (CYP2C19) polymorphism. The plasma metabolic ratio obtained from the concentrations of omeprazole plus omeprazole sulfone over 5′-hydroxyomeprazole was investigated.The time course of the omeprazole metabolic ratio was studied in 14 extensive metabolizers, one intermediate, and five poor metabolizers of CYP2C19 after a 1-week administration of 40 mg/d omeprazole. The ratio was then determined in 187 randomly selected Caucasian hospital patients and analyzed according to liver disease and co-medication.Between 1 and 4 h after omeprazole intake,the volunteers phenotyped by the urinary S/R-mephenytoin ratio were reliably identified as extensive metabolizers and poor metabolizers by an omeprazole metabolic ratio-antimode of 12. This antimode remained valid in eight extensive metabolizers and one poor metabolizer, who were re-investigated with 60 mg omeprazole b:i.d. for one week. Among 30 patients without concomitant drug intake, only one poor metabolizer (3.3%) was identified by both the S/R-mephenytoin ratio and omeprazole metabolic ratio. However, 30 of 47 patients with liver disease and 20 of 110 co-medicated patients without liver disease had a ratio >12. This highly exceeded the poor metabolizer frequency of 3–4% in Caucasians.Like other phenotypic tests, the omeprazole metabolic ratio appears to reflect CYP2C19 genotype reliably only in individuals without liver disease or co-medication. The omeprazole metabolic ratio may serve the double purpose of phenotyping for CYP2C19 and to individualize dosing in omeprazole-treated patients.